This is a competitive renewal application for funding of years 16-20 of P-01 AG 04875 "Physiology of Bone Metabolism in an Aging Population." Osteoporosis is one of the most important diseases associated with aging and one of the most important issues affecting women's health. Fractures due to osteoporosis exact a staggering toll in disability and expense. The lifetime risk of having one or more fractures associated with osteoporosis is 40%-50% for a White women and is one third of this for a Black woman or a White man. Each year osteoporosis causes at least 1.5 million fractures and costs the health care system $14 billion in the United States. Our overall goal is to understand the causes of age-related bone loss and osteoporosis better so as to develop more effective strategies for their treatment and prevention. This program grant application comprises projects employing different investigative disciplines and an administrative/statistical core that interact synergistically two permit more rapid progress than could be achieved by each alone. "Pathophysiology of Osteoporosis," is the clinical investigative component. Among the novel hypotheses that will be tested are whether the newly discovered anti-resorptive and pro-resorptive cytokines-osteoprotegrin and its cognate ligand-are the paracrine mediators of estrogen (E) action on bone and abnormalities in their secretion contribute to postmenopausal osteoporosis and whether E deficiency plays a major causal role in bone loss in aging men. "Risk Factors for Hip Fractures," the epidemiology component, features a series of unique, population-based retrospective (non-current, historical) cohort studies designed to assess the effects of certain diseases, drugs, and lifestyle differences on the incidence of fractures. "Sex Steroids, Growth Factors, and Bone Cell Function," the basic science component, focuses on sex steroid regulation of bone cell function. It will address two of the most important current issues in bone cell biology- the effect of changes in the concentration of the alpha and beta species of estrogen receptors on bone cell function and the identify of the major paracrine mediator of E on bone cells.